Imidazolinium compounds



Patented Jan. 3, 1950 v OFF-[cs IMIDAZOLINIUM CQMPOUNDS I Horace A. Shonle, Indianapolis, and Edwin E. Shepard, Beech Grove, Ind., assignors to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Drawing. Application July 19, 1946, Serial No. 684,779

Claims.

This invention relates to a group of new organic compounds and more particularly to new substituted dihydroimidazolium compounds. This application is a continuation-in-part of our prior application Serial No. 605,191, filed July 14, 1945, now abandoned.

These new substituted dihydroimidazolium compounds have surface tension depressing and bacteriostatic properties, and certain preferred compounds have therapeutic value for combating various bacterial invasions.

By this invention we have provided new compositions of matter which may be represented by the following formula:

wherein R is an aliphatic hydrocarbon residue having a carbon content within the range of 8 to 18 carbon atoms, R1 and R2 are the same or different aliphatic hydrocarbon radicals each having from 1 to '7 carbon atoms, the total number of carbon atoms in R and R1 being from to 25; X is an anion; and n is an integer from 1 to 3 inclusive.

The R substituent may be a particularhydrocarbon radical, or it may be a mixture corresponding to a commercial product from which it is derived, for example, one comprising a mixture of several homologous hydrocarbon compounds of differing numbers of carbon atoms within the range of 8 to 18 carbon atoms, or one consisting mainly of a particular hydrocarbon compound with smaller amounts of close homologues of such compound copresent. For example, the R substituent may be derived from the commercial alcohol Lorol, which is a mixture of alcohols of from 8 to 18 carbon atoms, in which case the R substituent may be considered to comprise a corresponding mixture. The R1 and R2 substituents may also contain such variations, but in most cases substantially pure starting compounds will be convenient for these shorterchain substituents.

The compositions of matter of our invention may be regarded as comprisin positively charged dihydroimidazolium cations which are substituted by aliphatic hydrocarbon radicals and which are combined with negatively charged anions. The aliphatic hydrocarbon groups may be selected from straight chain saturated,

branched chain saturated, and straight and branched chain unsaturated groups. The negatively charged anion associatedwith the dihydroimidazolium cation may be any one of a number of negative ions such as, for example, the chloride, bromide, sulfate, acetate, or phosphate'ions. By way of example, and referring to the above structural formula, when R is a dodecyl group,R1 an isoamyl group, R2 an allyl group, X a sulfate ion, and n is 2, the compound is di- (1 dodecyl 2 isoamyl- 3 allyl 4,5 dihydroimidazolium) sulfate.

In 'co'mpoundsof this invention the number of carbon atoms contained in the two groups R and R1 ranges from a total of 10 to about 25 carbon atoms. .The following example illustrates this limitation: When R1 is 'a hydrocarbon group containing 1 carbon atom, R must be a hydrocarbon group containing at least 9 carbon atoms, but it may contain any. number up to its own limit of 18 carbon atoms.

It should be noted that two isomeric forms of our'compounds exist simultaneously because of a dynamic equilibrium. Thus, compounds of our invention may be represented by either of the followin I formulas:

Formula B wherein R, R1, R2, X and n have the same significance as before. In Formula A, the nitrogen at positionl is tertiary, and the nitrogen at position 3 isquaternary. v In Formula B, the nitrogenat position 1 is quaternary, and the nitrogen in position 3 is tertiary. In the specification and claims-we employ for convenience Formula A, wherein R is attached to the tertiary nitrogen, at position 1, and R2 is attached to the quater-,

- nary nitrogen at position 3. It will be understood that both isomers illustrated are to be considered as within the scope of this invention.

The compounds of this invention have several fields of utility. For example, they are eifective in reducing the surface tension of aqueous solutions, and have bacteriostatic properties. Additionally, certain preferred compounds have therapeutic qualities which make them suitable for application in the treatment of various bacterial in-- vasion's. These preferred compounds are those of the foregoing formulas in which the R substituent is an aliphatic hydrocarbon residue having from 8 to not over 13 carbon atoms, the sum of the carbon atoms in R and R1 is from to 17, and the sum of the carbon atoms in R, R1, and R2 is not greater than 18. These preferred compounds are distinguished by their antibacterial properties and their low hemolytic effect. For example, a compound in which R is a I l-carbon radical and R1 and R2 are both methyl .is more than four times as hemolytic as saponin, whereas a corresponding compound in'which R isa 12-carbon radical is less than oneuhalf as hemolytic as saponin.

Broadly, we may prepare the compounds embodied in our invention by reacting a suitably substituted dihydroimidazole with a member of the class of alkylating agents such as, for example, the nitrates, sulfates or halides of aliphatic'hydrocarbons. Preferably, and because of their ready availability; we employ the'halidesby which we mean the chlorides, bromidesand iodides, and exclude the fluorides-and :thus xpreferably form compounds in which the .anion X'isa halogen anion-by which we mean chloride, bromide or iodide. The reactionis effected by mixing the substituted dihydroimidazole with the halide of the aliphatic hydrocarbon, allowing any spontaneous reaction to subside and subsequently heating the mixture to'complete' the'reaction. The product may be purified by recrystallization or precipitation from suitablesolvents or mixtures thereof. The theoretical amount of the aliphatic hydrocarbon halide may be used but it is preferable to use an excess to assure completion of the reaction. The reaction is conveniently, although not necessarily, carried out in a closed system thus eliminating any loss ofv the aliphatic hydrocarbon halide by-volatization. If desired,.a suitableznonreactive solvent such as, for example; alcohol or ethyl acetate may be used as a vehicle during the reaction.

In preparing the compounds ofour invention there may be used as starting material a mixture of similarly substituted dihydroimidazoles. Thus for example, referring to the above formulas, a group of dihydroimidazoles wherein R is a mixture of aliphatic hydrocarbon radicals having from 8-l8-carbon atoms and R1 isan aliphatic hydrocarbon group containing not more than 7 carbon atoms, may be reacted with a halide of-anv aliphatic hydrocarbon such as methyl'bromide to yield a mixture of the correspondingly substituted dihydroimidazolium bromides.

It should be noted that the compounds of our invention comprising both of two isomeric forms as mentioned heretofore may be prepared by either of two routes. A-dihydroimidazole substituted by the groups R and R1 may be alkylated with an Rz-containing alkylating agent. Likewise a dihydroimidazole substituted by the groups R1 and R2 may be alkylated by an R-containing alkylating agent. The same compound or mixture of compounds results whenR, R1, and R2 are correspondingly identical'in each alkylation reaction.

The compounds'of our invention are salt-like and generally water-soluble, and consequently are subject to many of the ionic reactions which typify soluble inorganic salts. By anionic interchange reactions, one anion mayrbe substituted for another. For example, by taking: advantage of the lower solubility of a substituted dihydroimidazolium sulfate as compared with the solubility of the corresponding imidazolium chloride,

'4 the sulfate may be crystallized preferentially from a solution containing the dihydroimidazolium, sulfate and chloride ions. Illustrating another method of efiecting this conversion, an aqueous solution of substituted dihydroimidazolium halide may be shaken with substantially insoluble silver sulfate, whereby the halide ion is removed as insoluble silver halide leaving in solution the dihydroimidazolium sulfate. Additionally, ionic interchange may be effected through the hydroxyl ion as an intermediate. Upon shaking an aqueous solution of a substituted dihydroimidazolium halide with silver oxide, there is formed the corresponding soluble dihydroimidazolium hydroxide and insoluble silver halide. Treatment of the soluble dihydroimidazolium hydroxide solution with the appropriate acid forms the desired dihydroimidazolium compound.

The following examples illustrate our invention.

Example 1 1-n-decyl-2,3dimethyl-4,5-dihydroimidazolium iodide represented by the formula may be prepared from 1-n-decyl-2-methyl-4,5-dihydroimidazole and methyl iodide as follows:

. 1-n-decyl-2-methyl-4,5-dihydroimidazole was prepared by heating a mixture of 203 g. :ofiN- acetyl ethylene diamine-and 560 g. of finely powdered calcium oxide to 225-235 C. for 14 hours. After cooling to -100'C. the mixture was extracted with three 500 cc. portions of alcohol. The alcohol was evaporated and the residue upon distillation at l198 C. yielded 2-methyl-4,5- dihydroimidazole. A mixture of 50.4 g. of 2- methyl-4,5-dihydroimidazole, 52.8 g. of n-decyl chloride and cc. of benzene was refluxed for seven hours and then cooled to 25 C. A solution of 24 g. of 50 percentsodium hydroxide solution in 150 cc. of water was added. the mixture filtered and the benzene layer-separated from the filtrate. The benzene was removed in vacuo and the crude 1 n decyl-2-me'thyl-4,5-dihydroimidazole distilled at l55-156 C./6 mm.

"A cold mixture of 1.8 g. of l-n-decyl-2-methyl- 4,5-dihydroimidazole and 1.7 g. of methyl iodide was sealed in a tubeand the tube was heated at IUD- C. for two hours. The tube was then cooled to room temperature, its contents dissolved in about 40 cc. of boiling ethyl acetate, and the solution treated with decolorizing carbon and filtered. Upon cooling the filtrate to'about 0 C., 1-n-decyl 2,3-dimethyl-4,S dihydroimidazolium iodide precipitated. It was recrystallized from ethyl acetate whereupon it meltedat about 103-104 C.

Example 2 l-n-decyl 2 -n -amyl 3 methyl-4,5-dihydroimidazolium iodide represented by the formula may be prepared by reacting l-n-decyl-2-n-amyl- 4,5-dihydroimidazole with methyl iodide as follows:

The .1-n-decyl 2-n-amyl-4,5-dihydroimidaz01e used in the preparation was prepared by methods analogous to' the preparation of l-n-decyl-Z- methyl-4,5-dihydroimidazole described in Examplel.

A cold mixture of 1.5 g. of l-n-decyl-Z-n-amyl- 4,5-dihydroimidazole and 1.7 g. of methyl iodide was sealed in a tube. Upon warming to about room temperature the contents of the tube reacted spontaneously, after which reaction the tube was heated to 110 C. for one hour. The tube: was then cooled to about room temperature, its contents dissolved in about 50 'cc. of hot ethyl acetate, the solution treated with decolorizing carbonand filtered. Cooling to C. produced no precipitate, whereupon petroleum ether was added to the solution to yield a precipitate of 1-n-decyl-2-n-amyl-3methyl-4,5-dihydroimida zolium iodide which separated as an oil. The oil was purified by dissolving it in ethyl acetate, treating with decolorizing carbon, filtering and adding an excess of petroleum ether to reprecipitate the 1-n-decyl-2-n-amyl-3-methyl-4,5-dihydroimidazolium iodide as an oil which was dried in a vacuum desiccator over sulfuric acid.

Example 3 1-n-dodecy1-2,3-dimethyl 4,5-dihydroimidazolium iodide represented by the formula 2CNCiz 2 -CHg I may be prepared by reacting 1-n-dodecy1-2- methyl-4,5-dihydroimidazole with methyl iodide according to the method used in the preparation of 2,3-dimethy1-1-n-decyl 4,5-dihydroimidazolium iodide described in Example 1.

1-n-dodecyl-2,3-dimethyl-4,5-dihydroimidazo lium iodide melted at about l-121 C.

The 1-n-dodecyl-2-methy1-4,5-dihydroimidazole used in the preparation was prepared by a method analogous to that used in the preparation of l-n-decyl-2-methy1-4,5-dihydroimidazole described in Example 1.

Example 4 l-n-tetradecyl-2,3-dimethyl-4,5 dihydroimid azolium iodide represented by the formula H: CH: I

may be prepared by reacting 1-n-tetradecy1-2- methyl-4,5-dihydroimidazole with methyl iodide by a method analogous to that used in the preparation of 1-n-decyl-2,3-dimethyl-4,5-dihydroimidazolium iodide described in Example 1.

The 1 n-tetradecy1-2,3-dimethyl-4,5-dihydroimidazolium iodide thus obtained melted at about 120-121 C.

Example 5 1-n-0ctadecyl-2,3-dimethyl-4,5, dihydroimidazolium iodide represented by the formula H C- NCia a1 H; CH I may be prepared by reacting 1-n-octadecyl-2- 6 methyl-{1,5-dihydroimidazole with methyl iodide in asealed tube according to the preceding examples.-

The l-n-octadecyl-2-methyl-4,5-dihydroimidazole used in the preparation is prepared by a method similar to that used in the preparation of 1-n-decyl-2-methyl-4,5-dihydroimidazole described in Example 1.

Example 6 A mixture of substituted dihydroimidazolium chlorides represented by the following formula in which R is an aliphatic hydrocarbon residue having a carbon content in the range of 8 to 18 carbon atoms, R1 and R2 are aliphatic hydrocarbon radicals each having from 1 to 7 carbon atoms, the sum of the carbon atoms in R and R1 being from 10 to 25, X is an anion, and n is an integer from 1 to 3 inclusive.

2. A composition of matter represented by the formula in which R is an aliphatic hydrocarbon residue having a carbon content in the range of 7 to 18 carbon atoms, R1 is an aliphatic hydrocarbon radical having from 1 to 7 carbon atoms, R2 is a saturated aliphatic hydrocarbon radical having from 1 to 7 carbon atoms, the sum of the carbon atoms in R and R1 being from 10 to 25, X is an anion, and n is an integer from 1 to 3 inclusive.

3. A composition of matter represented by the formula in which R is a mixture of aliphatic hydrocarbon radicals having from 8 to 18 carbon atoms, and Ha is a halogen anion other than fluorine.

4. A therapeutic composition comprising a composition of matter as defined in claim 1, in which the R substituent has not to exceed 13 carbon atoms, the sum of the carbon atoms in 1 8 the R and R1 substlbuents do flOt-EXOEGQ 1-7, and REFERENCES CITED the sum or the carbon items in the'R, R1, and R2 substituents does not exceed 18, and in which the The followin references r of recor in the anion X is a halogen aniOn' other than fluorine. file of this patent:

5. 1-ndecyl-2,3 -dimethy1-4,5 dihydroimidaz- 5 UNIT TENT ollum iodide represented by the formula. ED STATES PA 8 Number Name Date 2, 042,023 Schonhofer May 26, 1936 2,892,326 Kyrides Jan. 8, 1946 H1 43B! 1 10 2,404,299 Kyrides July 16, 1946 \/N\ 2,404,300 Kyrides July 16, 1946 0H, FOREIGN PATENTS HORACE A. SHONLE. Number Country Date EDWIN R. SHEPARD. 15 501,727 Great Britain Feb. 28, 1939 

1. A COMPOSITION OF MATTER REPRESENTED BY THE FORMULA 